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Vaccine 26S (2008) C4–C7
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Vaccine
journal homepage: www.elsevier.com/locate/vaccine
Evidences of parasite evolution after vaccination
Sylvain Gandon a,∗ , Troy Day b
a
b
CEFE - UMR 5175, 1919 Route de Mende, F-34293 Montpellier Cedex 5, France
Departments of Mathematics & Biology Jeffery Hall, Queen’s University, Kingston, ON K7L 3N6, Canada
a r t i c l e
i n f o
Article history:
Keywords:
Virulence
Vaccine
Escape mutant
Evolutionary medicine
Infectious disease
a b s t r a c t
We present a brief review of some of the empirical evidence of parasite evolution in response to vaccination. The available data shows that very different pathogen strategies can be selectively favored as a
result of vaccination. However, this data often lacks a qualitative and/or quantitative assessment of the
benefits and the costs associated with these alternative strategies. Without this type of information to calibrate theoretical models it will be difficult to predict the potential risks associated with vaccine-induced
evolution. Our purpose here is therefore to stimulate future research into quantifying these effects.
© 2008 Elsevier Ltd. All rights reserved.
Introduction
Vaccination is one of the most efficient health policies for protecting human and animal populations against infectious diseases
[1]. The immediate benefit associated with vaccination, however,
may be rapidly eroded if vaccine-adapted variants of pathogens
arise and spread in the population. But how likely is vaccine-driven
evolution? Here we discuss six different, well-studied examples
demonstrating the evolutionary potential of parasites in response
to vaccination.
Before getting into the details of the different case studies it
is necessary to lay out a clear and unambiguous language for
discussing and comparing the various examples. We refer to the
predominant strain (or strains) present prior to vaccination as the
‘wild-type’ strain, and to strains that are selectively favored in vaccinated hosts as ‘vaccine-favored variants’ (Fig. 1). The selective
advantage of a vaccine-favored variant in a vaccinated host is typically believed to arise from differences from the wild type in one or
more of three critical epidemiological parameters: its transmission
rate between hosts, the recovery rate of the host infected with such
a variant, and the mortality rate that the variant induces in the host.
It is also commonly believed that vaccine-favored variants suffer
some fitness cost in naı̈ve hosts (Fig. 1), since otherwise one would
expect them to reach appreciable frequencies, even in the absence
of vaccination. As with the benefit enjoyed by a vaccine-favored
variant, it is thought that this cost in naı̈ve hosts also arises from
differences from the wild type in one or more of the three epidemi-
∗ Corresponding author. Tel.: +33 4 67 61 34 23; fax: +33 4 67 41 21 38.
E-mail address: [email protected] (S. Gandon).
0264-410X/$ – see front matter © 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.vaccine.2008.02.007
ological parameters mentioned above. Not surprisingly, these costs
and benefits also play a central role in making predictions about
the evolutionary consequences of vaccination [2], and therefore we
focus predominately on them below.
For each of the six examples presented, we provide a brief background and then discuss the available evidence for how the costs
and benefits of vaccine-favored variants are realized. We note at
the outset, however, that aside from a very small number of experimental studies, most of the available evidence of vaccine-induced
evolution comes from uncontrolled, observational studies. As such,
it should be borne in mind that factors in addition to (or instead
of) vaccination might well have played a role in the evolution of
some of the parasites considered. Indeed, one of our main purposes
with this article is to stimulate future research aimed at quantifying
these costs and benefits.
Hepatitis B virus
There are six main genotypes (A–F) of human hepatitis B virus
(HBV), and they share a common immunodominant region on the
outer protein coat (surface antigen), termed the a determinant. The
neutralizing (protective) antibodies induced by vaccination target
epitopes located within the a determinant. The use of HBV vaccines started in the 1980s in developed countries and dramatically
reduced the incidence of the disease. However, there is now growing evidence that mutations occurring within the surface antigen
allow replication of HBV in vaccinated people. In 1990 a mutation
(a single amino acid substitution) in the S gene coding for the a
determinant of the surface antigen was described [3]. Since then,
several other HBV variants have been found in many countries.
Interestingly these mutants have also been identified in unvac-
S. Gandon, T. Day / Vaccine 26S (2008) C4–C7
Cost of
escape
Parasite fitness
Vaccine
efficacy
strain
mice than the wild type [8,9]. Furthermore, in naı̈ve mice the variants were found to have an overall lower performance than the wild
type (Ref. [9]; Mooi, personal communication). However, no information is available yet regarding the impact of these mutations on
the epidemiological parameters of transmission, recovery rate or
virulence.
Benefit of
escape
Wild type
C5
Vaccine-favored
strain
Figure 1. Schematic representation of the comparison between a wild-type strain
and a vaccine-favored variant. The lifetime reproductive success (a relevant measure of fitness at endemic equilibrium) is plotted in naı̈ve hosts (in black) and in
vaccinated hosts (in white) for both strains. The efficacy of the vaccine can be evaluated by the reduced performance of wild-type strain in vaccinated hosts. The cost of
adaptation to vaccination is evaluated in naı̈ve hosts while its benefit is evaluated in
vaccinated hosts (in both cases, relative to the performance of the wild-type strain).
cinated hosts [4], though in lower frequency than in vaccinated
individuals. This suggests that, although there is likely a cost associated with these variants (in terms of their fitness in naı̈ve hosts;
Fig. 1), it might be relatively small. The epidemiological models of
Wilson et al. [5,6] assume that the vaccine-favored variant remains
infectious to naı̈ve hosts but that its transmission rate is lower
than the wild type. Consistent with this hypothesis is the fact that
some escape variants have been shown to remain infectious and
pathogenic in unvaccinated chimpanzees [40]. Unfortunately there
is no experimental evidence on the nature and the magnitude of
these costs. Currently not much is known regarding the epidemiological parameters through which the vaccine-favored mutants
gain their advantage in vaccinated hosts, but it seems plausible that
they enjoy both an increased duration of infection (i.e., reduced
recovery) as well as an increased rate of transmission.
Pertussis
Pertussis (or whooping cough) is a highly transmissible bacterial infection of the respiratory tract, and was a major cause of
childhood morbidity and mortality in the prevaccination period.
In the 1950s several countries started mass vaccination programs
against Bordetella pertussis, with a whole cell vaccine made out of
different strains. This effectively reduced the incidence of pertussis, but in many countries pertussis remains an endemic disease.
Worse still, in some highly vaccinated populations the incidence
of pertussis has started to increase again since 1990s. It has been
suggested that this reemergence could be due to the spread of
vaccine-favored variants. For example, Mooi et al. [7,9] showed
that new mutations in two surface proteins, pertactin and pertussis toxin, have appeared after the start of vaccination, replacing the
variants which are found in the pertussis vaccines. Both proteins
are virulence factors and induce protective immunity in humans
and other animals. These mutations may thus be involved in evading the immune response induced by vaccination. In fact these new
variants were observed more frequently among vaccinated individuals than in unvaccinated individuals [7]. This suggests a potential
selective advantage in vaccinated hosts and/or a cost in naı̈ve ones.
Experimental results with vaccinated and unvaccinated mice are
partially consistent with this hypothesis. The more recent variants
perform relatively better (i.e., reach higher densities) in vaccinated
Streptococcus pneumoniae
S. pneumoniae consists of 90 known serotypes (types of capsular polysaccharides) with variable prevalence and virulence [10].
In contrast with HBV vaccines, pneumococcal vaccines have been
designed to target a subset of the circulating serotypes. The vaccines used in three clinical trials include only between 7 and 11
serotypes. Several studies reported a decrease in the incidence of
the disease but also showed evidence of serotype replacements
(reviewed in Ref. [11]). The serotypes that were not included in
the vaccines reached higher frequencies in vaccinated individuals
in three independent clinical trials of pneumococcal conjugate vaccines [12–14]. In this situation, the vaccine-favored variants were
already present at appreciable frequencies before vaccination, however, suggesting that the costs associated with these variants are
relatively low. As with the case of HBV vaccines, virtually nothing is known about the epidemiological parameters through which
the vaccine-favored mutants gain their advantage, but again it is
plausible that this comes about through both an increased duration
of infection (i.e., reduced recovery) and an increased transmission
rate.
Marek’s disease
Marek’s Disease Virus (MDV) is an avian herpes virus that causes
substantial losses in the poultry industry. Vaccination started in the
1950s but new virus strains rapidly emerged. These strains have the
ability to infect and exploit vaccinated birds. Witter [15] showed
experimentally that these emerging strains are more able to cause
disease than ancestral strains in both naı̈ve and vaccinated hosts.
However, in contrast with the previous examples, there is evidence
that these mutants are also much more virulent (i.e., they induce
more extreme symptoms) in both naı̈ve and vaccinated individuals
[15–17]. Interestingly, it appears as though subsequent generations
of vaccines have then been followed by even further increases in virulence. This increased virulence may be viewed as one component
of the cost (induced death may limit transmission) associated with
a better performance on vaccinated hosts. This particular disease
seems like a very promising case in which experimental quantification of the costs and benefits of vaccine-favored variants would
be readily possible.
Malaria
Several types of vaccines are currently developed against human
malaria [18–20]. Although there is not yet any conclusive indication of how these vaccines affect malaria evolution, at least one
study in humans has demonstrated that vaccination exerts selective
pressure in favor of strains not included in vaccines [21]. Furthermore, there is experimental evidence from rodent malaria that
vaccination can affect virulence evolution. Mackinnon and Read
[22] performed an experimental evolution study with the rodent
malaria Plasmodium chabaudi in laboratory mice. They evolved multiple lines of P. chabaudi in immunized and naı̈ve mice by repeated
serial passage of blood-stage parasites. After 20 passages they
observed that the lines that evolved in immunized mice became
more virulent in both naı̈ve and immunized mice. This suggests
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S. Gandon, T. Day / Vaccine 26S (2008) C4–C7
that these lines adapted to immunized mice by increasing their
level of host exploitation. In support of this hypothesis Mackinnon
and Read [23–25] showed that the more virulent strains persist at
higher densities and for longer. Thus, as for MDV, the more virulent strains could be viewed as vaccine-favored variants where the
cost associated with this adaptation would be the increased virulence in naı̈ve mice. The benefit of this increased virulence would be
a consequence of the covariances among the different life-history
traits [23–25] leading to increased transmissibility and decreased
recovery rate in immunized hosts.
Diphtheria
The bacteria Corynebacterium diphtheriae causes human respiratory infections, and the disease that it induces is caused by
toxin production. Although we failed to find any experimental evidence, it is generally assumed that toxin production (governed
by a tox gene carried by a bacteriophage) confers a competitive
advantage to the bacteria [26,27]. The synthesis of the toxin, however, carries metabolic costs. Toxin production may represent as
much as 5% of the total bacterial protein synthesized [28]. Diphtheria vaccines started to be used in the 1920s. The peculiarity
of these vaccines is that they are not directed towards the organisms producing the toxin but towards the toxin itself. Such toxoid
vaccines are made by treating the toxin with heat or chemicals
to destroy its ability to cause illness while retaining the capacity to stimulate protective immunity. From the parasite point of
view, this antitoxin immunity removes the benefit of producing
the toxin and, since this toxin is costly, could select for variants
that do not produce the toxin (i.e., tox− strains). These strains can
be viewed as vaccine-favored variants because, without paying the
cost of toxin production, they can exploit vaccinated hosts more
efficiently than the wild type (i.e., tox+ strains). Pappenheimer [26]
reports that this type of evolution may have occurred in Romania
where an intensive vaccination program was carried out between
1958 and 1972. During this period the fraction of immune individuals rose from 60 to 97%, while the morbidity fell from 600
per 100 000 to only one per 100 000 individuals. Interestingly, a
survey of the characteristics of the C. diphtheriae carried by the
population during the same period of time revealed that the proportion of the tox+ strains dropped from 87 to only 4%. In contrast,
in other countries, diphtheria remains endemic in spite of vaccination [29,30]. It should also be noted, however, that the potential
impact of the vaccine on toxin production remains controversial.
Given that the diphtheria toxoid vaccine is imperfect [31] the production of more toxin may be an alternative way to overcome the
effect of the toxoid. Depending on the magnitude of the cost and
the benefit associated with the toxin, vaccination may either select
for or against toxin production [17,32]. Unfortunately there does
not yet appear to be any quantitative estimates of these parameters.
Discussion
The above empirical examples show that vaccine-favored variants do occur and, in some cases, may even be implicated in the
reemergence of disease. Nevertheless, it is clear that there is a lack
of information regarding the nature and the magnitude of the costs
incurred by these mutants in naı̈ve hosts, as well as the benefits
that they gain in vaccinated hosts (see Fig. 1). These factors are
crucially important since they strongly influence the evolutionary
consequences of vaccination [2]. For example, previous theoretical
studies have demonstrated that if the costs paid by vaccine-favored
variants in naı̈ve hosts are expressed through increased virulence
(as seems to be the case in Marek’s disease and rodent malaria),
then we would expect vaccination to induce the evolution of higher
levels of virulence (when measured in naı̈ve hosts) because it drives
such variants to higher frequency (Refs. [33–36], see other papers
in this issue). On the other hand, if the costs are paid through other
epidemiological parameters such as reduced transmissibility, then
this is not typically the case [37–39,5]. Therefore one critical aspect
of future empirical work in this area will be to determine the nature
of these costs and benefits for different parasite strains. We hope
that this article, in some way, stimulates such research and motivates collaborative research projects between scientists studying
vaccines and evolutionary biologists.
Acknowledgements
We would like to thank Margaret Mackinnon, Frits Mooi and
Andrew Read for discussions and comments on an earlier draft
of this paper. S.G. was supported by the Centre National de la
Recherche Scientifique (France) and by an ANR grant ‘‘jeunes
chercheurs’’. T.D. was supported by a grant from the Natural Sciences and Engineering Research Council of Canada and the Canada
Research Chairs program (Canada).
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